Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Adv Exp Med Biol. 2021;1342:273-295. doi: 10.1007/978-3-030-79308-1_9.
Despite advances in the treatment of acute myeloid leukemia (AML), relapse is still widely observed and represents the major cause of death among patients with AML. Treatment options in the relapse setting are limited, still relying predominantly on allogeneic hematopoietic stem cell transplantation (allo-HSCT) and cytotoxic chemotherapy, with poor outcomes. Novel targeted and venetoclax-based combinations are being investigated and have shown encouraging results. Immune checkpoint inhibitors in combination with low-intensity chemotherapy demonstrated encouraging response rates and survival among patients with relapsed and/or refractory (R/R) AML, especially in the pre- and post-allo-HSCT setting. Blocking the CD47/SIRPα pathway is another strategy that showed robust anti-leukemic activity, with a response rate of around 70% and an encouraging median overall survival in patients with newly diagnosed, higher-risk myelodysplastic syndrome and patients with AML with a TP53 mutation. One approach that was proven to be very effective in the relapsed setting of lymphoid malignancies is chimeric antigen receptor (CAR) T cells. It relies on the infusion of genetically engineered T cells capable of recognizing specific epitopes on the surface of leukemia cells. In AML, different CAR constructs with different target antigens have been evaluated and demonstrated safety and feasibility in the R/R setting. However, the difficulty of potently targeting leukemic blasts in AML while sparing normal cells represents a major limitation to their use, and strategies are being tested to overcome this obstacle. A different approach is based on endogenously redirecting the patient's system cells to target and destroy leukemic cells via bispecific T-cell engagers (BiTEs) or dual antigen receptor targeting (DARTs). Early results have demonstrated the safety and feasibility of these agents, and research is ongoing to develop BiTEs with longer half-life, allowing for less frequent administration schedules and developing them in earlier and lower disease burden settings.
尽管急性髓系白血病（AML）的治疗取得了进展，但仍广泛观察到复发，这是 AML 患者死亡的主要原因。复发时的治疗选择有限，仍然主要依赖异基因造血干细胞移植（allo-HSCT）和细胞毒性化疗，预后较差。新型靶向治疗和 Venetoclax 为基础的联合治疗正在被研究，并取得了令人鼓舞的结果。免疫检查点抑制剂联合低强度化疗在复发和/或难治性（R/R）AML 患者中显示出令人鼓舞的缓解率和生存率，尤其是在 allo-HSCT 前后。阻断 CD47/SIRPα 通路是另一种策略，显示出强大的抗白血病活性，在新诊断的、高风险骨髓增生异常综合征和 AML 伴 TP53 突变的患者中，缓解率约为 70%，总生存期令人鼓舞。在淋巴恶性肿瘤的复发环境中被证明非常有效的一种方法是嵌合抗原受体（CAR）T 细胞。它依赖于输注能够识别白血病细胞表面特定表位的基因工程 T 细胞。在 AML 中，已经评估了具有不同靶抗原的不同 CAR 构建体，并在 R/R 环境中证明了其安全性和可行性。然而，在 AML 中，有力地靶向白血病blasts 而不损伤正常细胞的难度是其应用的主要限制，正在测试各种策略来克服这一障碍。另一种方法是基于内源性重定向患者的系统细胞，通过双特异性 T 细胞衔接器（BiTEs）或双抗原受体靶向（DARTs）来靶向和破坏白血病细胞。早期结果证明了这些药物的安全性和可行性，并且正在进行研究，以开发具有更长半衰期的 BiTEs，允许更频繁的给药方案，并在更早和更低疾病负担的情况下开发它们。
